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The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Wong, Edward H. Kemp, John A. Priestley, Tony Knight, Antony R. Woodruff, Geoffrey N. Iversen, Leslie L. |
| Copyright Year | 1986 |
| Abstract | The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant. |
| File Format | PDF HTM / HTML |
| DOI | 10.1073/pnas.83.18.7104 |
| PubMed reference number | 3529096 |
| Journal | Medline |
| Volume Number | 83 |
| Issue Number | 18 |
| Alternate Webpage(s) | http://www.pnas.org/content/83/18/7104.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1073/pnas.83.18.7104 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
